A deep understanding of ttie physiology and biophysics of fusion - and its disease relevance - requires a broad and comprehensive approach and relies heavily upon interdisciplinary approaches honed from a decade of studies of the mechanism of viral envelope fusion. These technologies - cell and molecular biology, surface force/adhesion biophysics, and optical imaging. The specific aims ofthe initial application covered four aspects of SNARE induced fusion: 1) SNARE distribution, mobility, and lateral interactions within the plane ofthe membrane. 2) Adhesive and molecular forces between SNAREs - determinants of transition states and the energetic. 3) Penultimate states of SNARE fusion: capturing the SNAREpin just before lipid-mixing, with a specific focus on the interplay between lipid structure and protein assembly. 4) Protein and lipidic determinants of fusion kinetics and pore formation. RELEVANCE (See instructions): This broad and comprehensive approach to elucidating the mechanism of intracellular membrane fusion by SNARE proteins will deepen our understanding ofthe physiology and biophysics effusion - and its key roles in diabetes.